Phenyl- and (substituted)-phenyl-1,2,3-triazole-alkanoic and -alkenoic acids

ABSTRACT

Certain phenyl- and (substituted)-phenyl-1,2,3-triazole-alkanoic and -alkenoic acids exhibit antiinflammatory or antipyretic activity.

United States Patent [1 1 Buckler et al.

[4 1 Aug. 19, 1975 PHENYL- AND (SUBSTITUTED )-PHENYL- l ,2,3-TRIAZOLE-ALKANOIC AND -ALKENOIC ACIDS [75] Inventors: Robert Thomas Buckler,

Edwardsburg, Mich.; Harold Eugene l-lartzler, Elkhart, Ind.; Shin Hayao,Tokyo, Japan; Gust Nichols,

[2]] App]. No.: 364,609

[52] US. Cl 260/308 A; 260/209 R; 260/349; 260/526 N; 424/269 [5 1] Int.Cl. C07D 249/06 [58 Field of Search 260/308 A [56] References CitedOTHER PUBLICATIONS Durden et al., J. Chem. Eng. Data, Vol. 9, pp.228-232, (1964), TPll4. Henseke et al., Chem. Abstracts, Vol. 66,Abstract No. 37841p, (1967), QDlA51.

Primary Examiner-Alton D. Rollins Attorney, Agent, or F irmMyron B.Sokolowski [57] ABSTRACT Certain phenyland (substituted)-phenyl-1,2,3-triazole-alkanoic and -alkenoic acids exhibit antiinflammatory orantipyretic activity.

2 Claims, No Drawings PI-IENYL- AND 4-(R,R)-phenyI-1,2,3,(2I-I)-triazole-2-(R -CO I-I); (SUBSTITUTED)-PHENYL- l,2,3-TRIAZOLE- ALKANOIC AND -ALKENOIC ACIDS SUMMARY OF THE INVENTION RThe chemical compounds of this invention are repre- 2 sented by generalstructural Formula I: J A

N J- 'L HO 0- R r1 In Formula I, R and R independently are hydrogen,loweralkyl, loweralkoxy, amino, loweralkylamino, loweralkylamido, orhalogeno R is hydrogen, loweralkyl, loweralkanoyl, or phenyl; R is aCI-I CI-I- {VJ CH CI-I CH CH or a CH=CI-I radical; and

How 5-(R',R )-phenyl-l,2,3,(1II)-triazole-1-(R CO H);

represents the triazole structures N 4 H R H "'1 N1) l I \N v r and U'-K Furthermore, the prefix loweras applied to appropri- 4-(R',R)-phenyl-l,2,3,( lH)-triazole-l-(RCO I-I); ate groups of R R and R meansone to three carbon and,

atoms. By definition, the atoms in the triazole ring are numbered in acounterclockwise manner with the nitrogen atom on the right side of thering designated as 7 (l), as in Formula II: R'

& I v11 4 R 1- 4 (3) 1 T' lJ (II) C-R H l-(R',R )-phenyl-l ,2,3,(lH)-triaZole-4(RCO H When R is other than hydrogen in Formula I, thefol- Because Formula I is asymmetncal there are five lowing representpreferred configurations thereof:

preferred arrangements of the (R',R )-phenyl and the loweralkanoic orloweralkenoic acid substituents (R )CO H around the triazole ring when Ris hydrogen. These preferred configurations are represented by f:() HFormulas III through VII respectively: I

The following specific compounds comprise preferred embodiments ofgeneral Formula I:

1 [4-phenyll ,2,3,(2H )-triazole-2]-acetic acid;

2. 3-[4-phenyl-1,2,3 ,(2I-I)-triazole-2]-propionic acid;

3. 4-[4-phenyll ,2,3,(2H)-triazole-2]-butyric acid;

4. 3-[4-( m-chloro )-phenyl-l ,2,3,(2I-I)-triazole-2]- propionic acid;

5. 3-[4-(m-bromo)-phenyl-l,2,3,(2H)-triazole-2]- propionic acid;

6. 3-[4-(m-methyl)-phenyl-l,2,3,(2I-I)-triaz0le-2]- propionic acid;

7. 3[4-(3,5-dichlor0)-phenyl-l,2,3(2H)-triazole-2]- propionic acid;

8. 3-[4-(m-acetamido )-phenyl- 1 ,2,3,( 2H )-triazole 2]-propionic acid;

9. 3-[2-phenyl-l,2,3(2H)-triazole-4]-propionic acid;

10. 3-[2-(m-chloro)-phenyl-l,2,3,(2H)-triazole-4]- propionic acid;

1 l. 3-[2-(m-bromo)-phenyl-l ,2,3,(2H)-triazole-4]- propionic acid;

12. 3-[ 2-phenyl'l ,2,3,( 2H )-triazole-4]-acrylic acid;

13. 3-[ 2-( m-chloro)-phenyl-l ,2,3,(2I-l)-triazole-4]- acrylic acid;

14. 3-[2-(m-bromo)-phenyl-l,2,3,(2H)-triazole-2]- acrylic acid;

15. 3-[5-phenyl-1,2,3,( lH)-triazole-l]-propionic acid;

16. 3-[5-(m-fluoro)-phenyl-1,2,3,(lH)-triazole-l]- propionic acid;

17. 4-phenyl- 1 ,2,3 1H )-triazolel-acetic acid;

18. 3-[4-phenyl- I ,2,3,( lH)-triazole-l ]-propionic acid;

19. 4-[4-phenyl-1 ,2,3 lH)-triazole-l ]-butyric acid;

20. 3-[4-( m-chloro)-phenyl-l ,2,3,( lH)triazole-l propionic acid;

21. 3-[4-(m-bromo)-phenyl-l ,2,3,( lH)-triazole-l propionic acid;

22. 3-[4-(m-fluoro)-phenyl-l ,2,3,( 1H)-triazole-1 propionic acid;

23. 3-[4-(m-methyl)-phenyl-l ,2,3,( 1H )-triazole-l propionic acid;

24. 3-[4-(m-ethoxy)-phenyl-l ,2,3,( lH)-triazole-l propionic acid;

25. 3-[4(m-amino)-phenyll,2,3,(1H)-triazole-l propionic acid;

26. 3-[4-(m-acetamido)-phenyll,2,3,( 1H)-triazolel ]-propionic acid;

Lil

27. 3-[ l-phenyl-1,2,3,( lH)-triazole-4]-propionic acid; 28.3-[1-(m-fluoro)-phenyl-l,2,3,(lH)-triazole-4]- bodiments of Formulas IIIthrough IX. Table I correlates the specific compounds with the generalFormulas. In Table I, each compound is identified by the numeralassigned above.

Table I Specific Compounds General Formula 1 thru 8 III 9 thru l4 IV l5and 16 V I7 thru 26 VI 27 thru 3l VII 32 thru 34 VIII 35 IX, X

Compounds having the configuration represented by Formulas V and V] aresynthesized by the thermal addition of (R ,R )-phenylacetylenes to azidoacids (J. A. Durden, Jr., et al., J. Chem. Eng. Data, 9:228 [1964]):

The mixture of isomers obtained from this reaction can be separated byfractional crystallization or by chromatography of the correspondingmethyl esters on silicic acid. The methyl esters can easily bereconverted into the free acids.

Compounds with structures corresponding to Formulas III and VI areformed when 4(R,R )-phenyltriazoles are alkylated with alphatic acidswhich contain an appropriate leaving group, X:

lsomers can be separated as described above.

Compounds with the arrangement of Formula IV are obtained by a number ofsteps bases on 2[(R,R

phenyl]-triazole-4-aldehydes (see Organic Synthesis Coll., Vol. B, p 429[1955]; and K. Ogura et al., Tet. Letters, 1383 [1972]):

Compounds with the configuration of Formula VII can be prepared by theaddition of (R,R phenylazides on acetylenic R -acids (E. Mugnaini etal., Atti. Accad. Nazl. Lincic., 14: 275 [1953]:

Compounds with the configuration of Formulas VIII thru X are prepared bythe following general method:

CE cu $11:

R -co H 2 1:1-R -co' H 1 '5 R 3 The phenyl and(substituted)-phenyl-l,2,3-triazolealkanoic and -alkenoic acidsrepresented by Formfula 1 exhibit antiinflammatory activity in theadjuvant arthritis (a modification of the method described in J.Pharmacol. Exptl. Therap., 178: 223, [1971]) or the pleural effusion(reported in Soc. Exptl. Biol. Med. 127: 597 [1963]) model ofinflammation in the rate.

The antiinflammatoryv activity of some of the compounds of thisinvention is listed in Table 2 as the value R/E, the ratio of theactivity of the reference drug (R), phenyl -butazone, to that of thecompound tested (E). In Table 2, the compounds are identified by thenumber preceding each in the above list of preferred embodiments ofFormula I. The symbols AA and PE signify the adjuvant arthritis andpleural effusion models of inflammation respectively.

Certain comppounds having Formula I also exhibit antipyretic activitywhen tested in rates at a dose of mg/kg according to the methoddescribed in Tox. Appl. Pharmacology, 22: 672 (1972).

""Tested at :1 dose of 100 mg/kgaccording to the method described inTox. Appl. PhurmucoL. 22: 672 (1972).

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES 1-8 The followingExamples have the configuration of Formula 111, described in the Summaryof the Invention:

(III) A solution of 40 g (0.28 moles) of 4-phenyltriazole, 31 g (0.28moles) of B-chloropropionic acid, and 22.4 g (0.56 moles) of sodiumhydroxide in 300 ml of water was refluxed for three days. Unreactedtriazole was removed by precipitation with carbon dioxide and the coldfiltrate acidifiediwith 5N HCl. The precipitate was three timesrecrystallized from isopropanol to give 10 g of fine white needles, mpI39143C.

Calculated for C I-N 0 C, 60,82; H, 5.11; N, 19.35. Found: C, 60.07; H,4.86; N, 19.21.

To a solution of g (0.22 g-atm) of sodium in 500 ml of methanol wasadded 29 g (0.2 mole) of 4-phenyl- 1,2,3 triazole followed by 24 g (0.22mole) of methyl chloroacetate. After 6 hours reflux, the solvent wasevaporated and the oily residue chromatographed on silica gel and elutedwith chloroform. The fast moving material was collected and hydrolyzedby refluxing with HCl/acetic acid to give the 7 g of the desired acid,mp. 199C, after recrystallization from aqueous methanol.

Calculated for C H N O C, 59.10; H, 4.46; N, 20.68. Found: C, 59.00; H,4.50; N, 20.88.

The following compounds were similarly prepared:

3-[4(m-Acetamido)-Phenyl)-1,2,3,(2H.-Triazole-2)- Propionic Acid: R NHCOCH R H, R -CH CH M.P. 172l73C. Calculated for C H ClN O C, 52.70; H,4.00; N, 16.71 Found: C, 52.34; H, 3.86; N, 16.66.

M.P. 9899C. Calculated for C H N O C, 62.32; H, 5.66; N, 18.18. Found:C, 62.47; H, 5.84; N, 18.35.

M.P. 90C. Calculated for C H BrN O C, 44.61; H, 3.40; N, 14.19. Found:C, 44.16; H, 3.31; N, 14.10.

M.P. 93C. Calculated for C H N O C, 62.32; H, 5.67; N, 18.18 Found: C,62.29; H, 5.79; N, 18.29.

M.P. l22123C. Calculated for C H Cl N O C, 46.17; H, 3.17; N, 14.69.Found: C, 46.10; H, 2.88; N, 14.71.

EXAMPLES 91 4 Examples 9-14 have the molecular arrangement of Formula1V, disclosed in the Summary of the Invention:

Pure m-chlorophenylhydrazine hydrochloride, 100 g (0.44 moles) wasconverted to the free base and added to a solution of 36 g (0.2 moles)of fructose in 75 ml glacial acetic acid and 200 ml of water. Thesolution was heated to 60C for 4 hours under N then cooled and filtered.This gave the m-chlorophenylosazone of fructose as a yellow solid whichwas immediately dissolved in 600 ml of hot dioxane and added to a hotsolution of 130 g (0.5 moles) of copper sulfate pentahydrate. After onehour at reflux, the black solution was cooled and the dark precipitaterecrystallized from methanol with charcoal treatment. This gave 6 g ofmchlorophenylosotriazole as fine white needles, m.p., l96197C.

A portion of this osotriazole, 1.86 g (0.0062 moles), was added to asolution of 5.7 g (0.025 moles) of periodic acid in 100 ml of water.After 16 hours, the solution was evaporated to near dryness and theresidue diluted with 200 ml of water. The white precipitate wasrecrystallized from pentane to give 0.9 g of 2-(3- chlorophenyl)-l,2,3,( 2H )-triazole14carboxaldehyde as fine white needles, m.p., 89C.

Calculated for C H N C10: C, 52.06; H, 2.91; N, 20.24. Found: C, 51,97;H, 2.82; N, 19.90.

Material from several runs was combined to give 8 g (0.039 moles) ofaldehyde which was heated for 2 hours with 7.8 g (0.078 moles) ofmalonic acid and 20 ml of pyridine containing 1 ml of piperidine. Aftercooling, the solution was diluted with 500 m1 of cold lNHCl and theprecipitate collected and dried. Recrystallization from ethanol gave 7.3g of the desired acrylic acid as white needles, m.p., 183C.

Calculated for C H N Cl0 C, 52.92; N, 3.23; N, 16.83. Found: C, 53.18;H, 3.16; N, 17.05.

The grams (0.047 moles) of 3-[2-phenyll ,2,3,(2H)- triazole-4]acrylicacid was hydrogenated at 50 psi over Raney nickle catalyst at roomtemperature. Recrystallization from benzene-heptane gave 7.8 g 77%) ofwhite needles, m.p. 76C. The starting material is a known compound (J.L. Riebsomer and G. Sumrell, J. Org. Chem. 13: 807 [1948]).

Calculated for C H N O C, 60.82; N, 19.35; H, 5.11. Found: C, 61.22; N,19.73; H, 5.22

The following were prepared by a similar synthesis:

'Calculated for C H,,N O C, 61.39; N, 19.53; H, 4.21. Found: C, 61.44;N, 19.88; H, 4.20.

9 3-[2-(m-Ch1orophenyl)-l,2,3,(2H)-Triazole-4]- Acrylic Acid: R Cl(meta), R H, R ,CH=CH; M.P., 183C. Calculated for C,,H,,C1N O C, 52.92;N, 16.83; H, 3.23. Found: C, 53.18; N, 17.05; H, 3.16.

3-[2-(m-Bromo)Phenyl-l,2,3,(2H)-Triazole-4]- Propionic Acid: R Br, R H,R CH CH M.P., 9697C. Calculated for C, H BrN O C, 44.61; H, 3.40; 14.19.Found: C, 44.33; H, 3.33; 14.23.

M.P. 229C. Calculated for C H BrN O C, 44.92; H, 2.74; N, 14.29. Found:C, 45.06; H. 2.72; N, 14.05.

EXAMPLES 26 Examples 1526 have the configuration of Formulas V and V1,described in the Summary of the Invention:

and

A. 3-[5-Phenyl-1,2,3,( lH)-Triazole-1]-Propionic Acid (Formula V): R H,R CH CH B. 3-[4-Phenyl-1,2,3,(1H)-Triazole-1]-Propionic Acid (FormulaV11): R H, R -CH --CH A. A solution of 35 g (0.34 moles) ofphenylacetylene and 44 g (0.34 moles) of methyl ,B-azidopropionate in100 ml of toluene were refluxed 16 hours. Upon cooling, 33 g of acrystalline product separated, m.p., l l2l 15C. Evaporation of themother liquor gave 35 g of an amber oil.

The amber oil was refluxed one hour in a solution of 11 g NaOH in 175 mlof 60% aqueous methanol. The product was precipitated with mineral oiland recrystallized twice from aqueous methanol to give 24 g of the typeV as white crystals, m.p., 181C.

Calculated for C H N O C, 60,82; H, 5.11; N, 19.35. Found: C, 60.84; H,5.05; N, 19.93.

B. The crystalline ester was hydrolyzed in like manner to give the typeV11 acid. After three recrystallizations from methanol-benzene thisamounted to 6.5 g, m.p., 141C.

Calculated for C H N O C, 60.82; H, 5.11; N, 19.35. Found: C, 60.56; H,5.09; N, 19.98.

3-[4-(3-Acetamido)Pheny1-1,2,3,(lH)Triazole-1]- Propionic Acid: R CHCONH, R H, R CH CH 3-[4-(3-Nitrophenyl)-1,2,3,(1H)-triazole-1]-propionic acid was esterified with isopropanol to give 34 g of isopropyl3-[4-(3-nitrophenyl)-1,2,3,(1H)- triazo1e-1]propionate, m.p. 112C.

Calculated for C A-1 N 0 C, 55.25; H, 5.30; N, 18.41. Found: C, 55.06;H, 5.18; N, 18.63

This ester (34 g, 0.1 1 mole) was hydrogenated in ethanol with Pd/C. Anoil was obtained which was hydrolyzed directly by heating for 3 hours in250 ml concentrated HCI. The acid solution was evaporated and theresidue taken up in water. The free base was precipitated with sodiumacetate. Recrystallization from aqueous ethanol gave 21 g of3-[4-(3-aminophenyl)- 1,2,3,(1H)-triazole-1]-propionic acid, m.p. 178C.

Calculated for C H N O C, 56.88; H, 5.21; N, 24.14. Found: C, 56.20; H,5.25; N, 25.25

The above acid (1 1 g, 0.047 moles) was dissolved in ml of hot glacialacetic acid containing 6.5 ml of acetic anhydride. After one hour, thereaction was cooled and filtered. Recrystallization from aqueous aceticacid gave 11.5 g of 3-[4-(3-acetamido phenyl)-1,2,3,(1H)-triazole-1]-propionic acid, m.p. 237C.

Calculated for C, H N O C, 56.92; H, 5.15; N, 20.48. Found: C, 56.54; H,5.24; N, 20.50. The following compounds were synthesized in a similarfashion:

3-[5-(3-Fluoro)-Phenyl-1,2,3,( lH)-Triazole- 1]Propionic Acid: RF(meta), R H, R -CH CH M.P., l47148C. Calculated for C H FN O C, 56.17;H, 4.29; N, 17.87. Found: C, 56.19; H, 4.29; N, 18.24.

M.P., 200C. Calculated for C H N O C, 59.10; N, 20.68; H, 4.46. Found:C, 58.56; N, 20.71; H, 4.36.

Calculated for C l-l ClN O C, 52.70; N, 16.71; H, 4.00. Found: C, 52.85;N, 16.84; H, 4.01.

3-[4-(m-Bromo)-Phenyl-1,2,3,( 1H)-Triazole- 1]Propionic Acid: RBr(meta), R H, R -CH CH M.P., 179C. Calculated for C l-ll BrN O z C,44.62; H, 3.40; N, 14.19. Found: C, 44.53; H, 3.38; N, 14.47.

Calculated for C H FN O C, 56.17; H, 4.29; N, 17.87. Found: C, 56.38; H,4.25; N, 18.08.

3-[4-(m-Methy1 )-Phenyll ,2,3,( 1H )-Triazole- 1]Propionic Acid: RF(meta), R H, R CH CH M.P., 143C.

Calculated for C, H,;,N O C, 62.32; H, 5.67; N, 18.17. Found: C, 62.56;H, 5.71; N, 18.22.

M.P., 138C. Calculated for c,,H,,N,o,; C, 59.76; H, 5.79; N, 16.08.Found: C, 59.37; H, 5.62; N, 16.40.

M.P., l77-178C.

Calculated for C H N O C, 56.88; N, 24.14; H, 5.21. Found: C, 56.20; N,24.25; H, 5.25.

3-[4-Phenyl-1,2,3,(lH)-Triazole-1]Butyric Acid: R

M.P. 136C.

Calculated for C H N O C, 62.32; H, 5.66; N, 18.18. Found: C, 62.47; H,5.65; N, 18.40.

EXAMPLES 27-31 The following examples have the configuration of FormulaV11, described in the Summary of the lnven- Mon:

v11). no c-R A solution of 12 g (0.056 moles) of the above acrylic acidin 500 ml of dilute aqueous sodium bicarbonate was hydrogenated at roomtemperature with Raney nickel catalyst at 100 psi. After acidification,the product was recrystallized from aqueous ethanol to give 1 l g of thedesired propionic acid as white crystals, m.p., 138C.

Calculated for C H N O C, 60.82; H, 5.11; N, 19.35. Found: C, 61.01; H,5.12; N, 19.84.

The following compounds were similarly prepared:

M.P., 134C. Calculated for C H FN O C, 56.18; H, 4.29; N, 17.87. Found:C, 56.37; H, 4.30; N, 18.54.

M.P., 166C. Calculated for C H ClN O C, 52.49; H, 4.00; N, 16.70. Found:C, 52.24; H, 3.92; N, 17.42.

3-[ l-Phenyl-1,2,3,( 1H) triazole-41acrolein, 31 (0.15 moles) wasprepared and oxidized to the corresponding acrylic acid with basicsilver oxide in water. After recrystallization from DMF-water thisamounted to 12 g of white crystals, m.p., 279C.

EXAMPLES 32-34 Examples 32-34 are representative of Formula V111,described in the Summary of the Invention:

(VIII) A mixture of 30 g (0.21 mole) of acetylphenylacetylene and 24 g(0.21 mole) of trimethylsilyl azide was heated at C for 24 hours. It wasthen cooled, dissolved in ether, and extracted with dilute sodiumhydroxide. This aqueous layer was separated and made acidic with diluteHCl. The precipitate was recrystal' lized from benzene-petroleum etherto give 1 1 g (28% of 4-acetyl-S-phenyltriazole, m.p. l 171 18C.

This material was combined with 2 g from a previous run to give a totalof 13 g (0.07 moles). It was dissolved in 200 m1 of absolute methanolcontaining 1.9 g (0.083 g-atom) of sodium. The methanol was evaporatedand the residue taken up in ml of dimethylformamide, cooled to 0C, and 6g (0.083 moles) of B-propiolactone was added. After stirring overnightat room temperature, the solution was concentrated, diluted with water,and the acid precipitated with dilute HCl. Recrystallization frompetroleum ether gave 5 g (30%) of the desired acid, M.P., 110l13C.

Calculated for C H N O C, 60.46 H, 4.68; N, 16.27. Found: C, 60.63; H,5.11; N, 16.54.

The following compounds were synthesized by a similar pathway:

M.P., 1l4115C. Calculated for C H N O C, 62.32; H, 5.66; N, 18.18.Found: C, 62.24; H, 5.54; N, 18.52

3-[4,5-Diphenyl-l,2,3,(2H)-Triazole-2]-Pr0pionic Acid: R H, R H, Rphenyl, R =CH CH M.P., l65-166C.

Calculated for C, H, F,N:,O C, 69.61; H, 5.15; N. 14.33. Found: C,69.11; H, 4.92; N, 14.29.

EXAMPLE 35 NaOH in an additional 250 ml water. After 18 hours at Thisexample i a preferred embodiment of Fo la 80C, the solution was cooledand acidified. A sticky lX and X, described in the above Summary of theInprecipitate formed which was taken up in ether and exvention: tractedwith sodium bicarbonate solution. Acidification3-[4,5-Diphenyl-l,2,3,(1H)-Triazole-l]-Propionic gave 36.5 g of crudeacid which was esterfied with a Acid: R H, R H, R phenyl, R borontrifluoride-methanol complex and chromato- 2- 2- 20 graphed on silicagel. This gave 21 g of methyl 3-[4,5-

A mixture of 50 g (0.28 moles) of diphenylacetylene diphenyll2,3(2H)triazole'z]'propionate' and 33 g (0.28 moles) oftrimethylsilylazide was heated Hydrolysis in dilute hydrochloric acidgave after at 150C for several days. The cooled reaction mixturecrystallization from aqueous methanol 1 l g of the was extracted withhot dilute NaOl-l. This was washed 25 sired acid -p with toluene whilestill warm, cooled, and acidified. Calculated for 11 1s s 2 C, H, N,

The precipitate was recrystallized from toluene to give 1433- Found: C,H, -29- 17 g of 4,5-diphenyl-l,2,3( 1H)-triazo1e, mp. 131C. What isClaimed Material from several runs was combined to give 41.5 L 'P y1H)'tfiaZ0le-1 l-P p g (0.19 moles). This was dissolved in 400 ml ofwater 30 acidat 80C containing 7.5 g (0.19 moles) sodium hydrox- 'i P yl-P p ide, and to the solution was added 20.5 g (0.19 moles) acid of3-chloropropionic acid and 7.5 g (0.19 moles) of

1. 3-(5-PHENYL-1,2,3, (IH)-TRIAZOLE-1)-PROPIONIC ACID. 2.3-(4,5-DIPHENYL-1,2,3, (2H)-TRIAZOLE-1)-PROPIONIC ACID.